The Neuropathology Core has evolved as a distinct functional entity within the Neuropathology Research Laboratory (NRL) in the Department Pathology. The NRL and Neuropathology Core are directed by Dr. Stephen DeArmond who has collaborated with Dr. Stanley Prusiner for the past eight years. Studies in the NRL have suggested that prpsc causes the characteristic pathological changes seen in prion diseases and that the rate of accumulation of PrPSc in the brain correlates directly with scrapie incubation time. These findings are relevant to other key issues in the prion hypothesis such as the scrapie species barrier, scrapie prion strains, and spontaneous prion diseases. The importance of the amino acid sequence of the prion protein (PrP) to those concepts is being tested in transgenic (Tg) mice that express different PrP constructs. Twenty to 30 different constructs will be tested each year. The increased numbers of animals being studied as a result of the success of this model and the increasing sophistication of the neuropathological analysis have significantly increased the demands on the Neuropathology Core function. Groups of Tg mice are analyzed in two ways: first, by classical neuropathological techniques using standard histological strains and immunohistochemistry with PrP and glial fibrillary acidic protein antibodies to identify the location and quantify the degree of spongiform degeneration, nerve cell loss, reactive astrocytic gliosis and amyloid plaque formation and, second, by a newly developed histoblot technique to measure the rate of accumulation and pattern of spread of PrPSc in the brain. Through this integrated analysis, the Neuropathology Core is not only providing confirmation of diagnosis but also contributing significantly to the full understanding of the pathogenesis of prion diseases.